Biomedical subjects

A Marchetti

Publications and source records attributed to A Marchetti.

At least 37 records · Page 2Linked to original sources

PubMed2000

Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumour cells.

The aim of the present study was to assess the cytotoxicity of manumycin, a specific inhibitor of farnesyl:protein transferase, as well as its effects on protein isoprenylation and kinase-dependent signal transduction in COLO320-DM human colon adenocarcinoma which harbours a wild-type K-ras gene. Immunoblot analysis of isolated cell membranes and total cellular lysates of COLO320-DM cells demonstrated that manumycin dose-dependently reduced p21 ras farnesylation with a 50% inhibitory concentration (IC50) of 2.51 +/- 0.11 microM and 2.68 +/- 0.20 microM, respectively, while the geranylgeranylation of p21 rhoA and p21rap1 was not affected. Manumycin dose-dependently inhibited (IC50 = 2.40 +/- 0.67 microM) the phosphorylation of the mitogen-activated protein kinase/extracellular-regulated kinase 2 (p42MAPK/ERK2), the main cytoplasmic effector of p21ras, as well as COLO320-DM cell growth (IC50 = 3.58 +/- 0.27 microM) without affecting the biosynthesis of cholesterol. Mevalonic acid (MVA, 100 microM), a substrate of the isoprenoid synthesis, was unable to protect COLO320-DM cells from manumycin cytotoxicity. Finally, manumycin 1-25 microM for 24-72 h induced oligonucleosomal fragmentation in a dose- and time-dependent manner and MVA did not protect COLO320-DM cells from undergoing DNA cleavage. The present findings indicate that the inhibition of p21ras processing and signal transduction by manumycin is associated with marked inhibition of cell proliferation and apoptosis in colon cancer cells and the effect on cell growth does not require the presence of a mutated ras gene for maximal expression of chemotherapeutic activity.

Alkyl and Aryl Transferases↗

PubMed1999

p53 inhibits alpha 6 beta 4 integrin survival signaling by promoting the caspase 3-dependent cleavage of AKT/PKB.

Although the interaction of matrix proteins with integrins is known to initiate signaling pathways that are essential for cell survival, a role for tumor suppressors in the regulation of these pathways has not been established. We demonstrate here that p53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase AKT/PKB. Specifically, we show that the alpha6beta4 integrin promotes the survival of p53-deficient carcinoma cells by activating AKT/PKB. In contrast, this integrin does not activate AKT/PKB in carcinoma cells that express wild-type p53 and it actually stimulates their apoptosis, in agreement with our previous findings (Bachelder, R.E., A. Marchetti, R. Falcioni, S. Soddu, and A.M. Mercurio. 1999. J. Biol. Chem. 274:20733-20737). Interestingly, we observed reduced levels of AKT/PKB protein after antibody clustering of alpha6beta4 in carcinoma cells that express wild-type p53. In contrast, alpha6beta4 clustering did not reduce the level of AKT/PKB in carcinoma cells that lack functional p53. The involvement of caspase 3 in AKT/PKB regulation was indicated by the ability of Z-DEVD-FMK, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in AKT/PKB levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of AKT/PKB in vitro. In addition, the ability of alpha6beta4 to activate AKT/PKB could be restored in p53 wild-type carcinoma cells by inhibiting caspase 3 activity. These studies demonstrate that the p53 tumor suppressor can inhibit integrin-associated survival signaling pathways.

Antigens, Neoplasm↗

PubMed1999

Activation of p53 function in carcinoma cells by the alpha6beta4 integrin.

The interaction of integrins with extracellular matrix is known to promote cell survival by inhibiting apoptotic signaling. In contrast, we demonstrate here that the alpha6beta4 integrin induces apoptosis in carcinoma cells by stimulating p53 function. Specifically, we show that expression of alpha6beta4 in carcinoma cells that lack this integrin stimulates an increase in the transactivating function of p53 as demonstrated by the ability of this integrin to up-regulate the expression of a p53-sensitive reporter gene as well as the endogenous p53 response gene, bax. In addition, we report that alpha6beta4 triggers apoptosis in carcinoma cells that express wild-type but not mutant p53 and that these alpha6beta4 functions are inhibited by a dominant negative p53 construct. Importantly, we provide a link between integrin signaling and p53 activation by demonstrating that the clustering of alpha6beta4 with a beta4 integrin-specific antibody promotes p53-dependent apoptosis in cells that express both alpha6beta4 and wild-type p53. These studies are the first to demonstrate that a specific integrin can promote apoptosis by activating p53. Moreover, given the ability of alpha6beta4 to stimulate invasion (Shaw, L. M., Rabinovitz, I., Wang, H. F., Toker, A., and Mercurio, A. M. (1997) Cell 91, 949-960), these studies suggest that the ability of alpha6beta4 to promote carcinoma progression will be enhanced in tumor cells that express mutant, inactive forms of p53.

Antigens, Surface↗

PubMed1999

A percutaneous large-needle aspiration biopsy technique for histologic examination of the testis in infertile patients.

OBJECTIVE: To describe a relatively new percutaneous large-needle aspiration biopsy technique for histologic examination of the testis in infertile patients. DESIGN: Retrospective analysis of clinical and pathologic data. SETTING: Clinical and academic research environment. PATIENT(S): Sixty-six infertile patients who underwent testicular biopsy. INTERVENTION(S): Local anesthesia was induced through spermatic cord block with lidocaine, and a relatively large needle (usually 18- or 20-gauge) was introduced percutaneously into the testicle without a scrotal incision. MAIN OUTCOME MEASURE(S): The number of seminiferous tubules per histologic section of each testicular biopsy sample. RESULT(S): A mean of 74 seminiferous tubules were obtained in the histologic sections of each biopsy sample. This number varied according to the size of the needle used; it was 24.7 when a 21-gauge needle was used, 56.2 when a 20-gauge needle was used, and 103 when an 18-gauge needle was used. The biopsies were performed in the office. No significant hematomas occurred, no antibiotic prophylaxis was prescribed, and no postbiopsy medical or pharmacologic interventions were required. CONCLUSION(S): Tissue specimens as large as those obtained with open surgical biopsy can be obtained from the testicles of infertile patients with the use of a percutaneous technique that is easier, less costly, and safer than any previously reported.

Adult↗

PubMed1999

Impact of palivizumab on expected costs of respiratory syncytial virus infection in preterm infants: potential for savings.

In its clinical assessment of the respiratory syncytial virus (RSV)-specific monoclonal antibody palivizumab, the IMpact-RSV Study Group demonstrated a reduction in hospitalizations for RSV-related lower respiratory tract infection in infants who received prophylaxis compared with infants who did not receive prophylaxis. An assessment of the RSV-related expenses for managing both groups of infants is needed to provide insight into the value of prophylaxis. The present study was conducted to identify and compare RSV-related health care expenditures incurred by infants who did not receive prophylaxis throughout one RSV season and after. Using a decision-analytic model populated with data from the contemporary medical literature, a pharmacoeconomic study was conducted from the perspective of the payer. Probabilities for RSV-related hospitalizations of infants who did and did not receive prophylaxis were abstracted from several published studies. Components of inpatient and outpatient care were identified through examination of hospital records, reviews of the published literature, and consultation with expert clinicians. Charges related to prophylaxis and medical management of infection were abstracted from hospital billing records and published data. Appropriate charges were applied to decision-tree branches and multiplied by in-line probabilities for outcomes. Products at terminal nodes were summed to establish total expected charges for both groups of infants. Widespread clinical use of prophylactic palivizumab would result in incremental expenses < or =$3459 per infant or cost savings < or =$39,107 per infant. The variability in value of prophylaxis derives from the rate of RSV-related hospitalizations in the community and the total health care expense of managing infected infants.

Antibodies, Monoclonal↗

PubMed1999

Lung tumours from non-smoking subjects: A p53-related genetic instability in a subset of cases.

Tumours developed in non-smoking patients represent about 10% of all lung neoplasms and show peculiar morphologic and genetic features. In a previous study, we found a constant association between p53 gene alterations and loss of heterozygosity (LOH) at the FHIT locus in a subset of non-smoking tumours (7 cases out of 35 analyzed), so we hypothesized that a genomic instability associated with p53 mutations could be the cause of FHIT LOH in these neoplasms. To test this hypothesis, in the same panel of tumours, we investigated the presence of LOH at 7 other microsatellite loci located on different chromosomes. Interestingly we found that all of the tumours with p53 alterations and LOH at the FHIT locus showed loss of heterozygosity at all of the informative tested loci. This association was statistically significant (p=0.0001). Our data indicate the presence of a generalized genomic instability in this subset of lung tumours. Since p53 alterations were mostly G:C --> A:T transitions and frameshift deletions, we are tempted to hypothesize that the genomic instability observed in non-smoking patients could be caused by particular p53 alterations. In fact, other kind of p53 mutations (G:C --> T:A transversions), frequently found in a series of 35 tumours of smokers used as control, were not associated with LOH at microsatellites loci. However, we cannot exclude that p53 alterations are a consequence and not the cause of the genomic instability. In this case, we have to admit that a gene(s), upstream of p53, is implicated in genome destabilisation in a subset of lung adenocarcinomas developed in non-smoking patients.

Female↗

PubMed1999

Telomerase activity as a prognostic indicator in stage I non-small cell lung cancer.

Patients with stage I non-small cell lung cancer (NSCLC) are typically treated with surgical resection alone. However, about one-third of such patients develop disease recurrence and die within 5 years after complete resection. The ability to predict recurrence could represent an important contribution to treatment planning. This study evaluates the presence of telomerase activity in tumor cells as a predictor of disease recurrence and cancer-related death after operation for stage I NSCLC patients. The activity of the telomerase enzyme was investigated by telomeric repeat amplification protocol (TRAP) in tumors and matching normal lung tissue samples obtained from 107 consecutive operable patients with pathological stage I NSCLC. Telomerase activity was detected in 66 (62%) of the 107 tumors examined and in none of the corresponding adjacent noncancerous lung tissue samples. Correlation with pathological parameters showed that telomerase activity was associated with histopathological grade (P = 0.0135) but not with tumor size or histological type. Univariate survival curves, estimated using the method of Kaplan and Meier, defined a significant association between telomerase activity and both disease-free survival (P = 0.0115) and overall survival (P = 0.0129). In multivariate analyses, performed by Cox's proportional hazards regression models, the presence of telomerase activity was the only strong predictor of disease-free survival (P = 0.0173) and overall survival (P = 0.0187). Our data indicate that telomerase activity can be an important prognostic factor that should be considered in future prospective trials of adjuvant therapy for high-risk stage I NSCLC patients.

Adenocarcinoma↗

PubMed1998

Microsatellite alterations and p53, TGFbetaRII, IGFIIR and BAX mutations in sporadic non-small-cell lung cancer.

Fifty-two sporadic primary non-small-cell lung carcinomas (NSCLC) were examined for microsatellite instability. Six different microsatellite markers localized on chromosomes 2, 5, 8, 10, 11 and 17 were used. Genomic instability was observed in 35% (18/52) of NSCLC at single or multiple loci. The tumors were also analyzed for p53-gene mutations by PCR-SSCP analysis. Polynucleotide stretch frameshift mutations of TGFbetaRII (transforming-growth-factor-beta receptor II), IGFIIR (insuline growth-factor II receptor) and BAX genes were also analyzed. RER+ (replication-error-positive) tumors appear not to be affected by a higher rate of point mutations in coding sequences: no correlation was found between microsatellite instability and point mutations in the p53 gene, and the RER+ tumors showed no alterations in stretches of nucleotide inside TGFbetaRII, BAX or IGFIIR.

Carcinoma, Non-Small-Cell Lung↗

PubMed1998

Cyclin D1 and retinoblastoma susceptibility gene alterations in non-small cell lung cancer.

Among the major regulators of the G1 restriction point are cyclin D1 and the retinoblastoma gene product (RB). In non-small cell lung cancer (NSCLC), the cyclin D1 gene is amplified/over-expressed in almost 50% of cases, and RB is inactivated in 6-32% of cases. It is of interest to evaluate concurrently the alterations of both genes on the same series of NSCLCs, to investigate whether cyclin D1 and RB alterations are alternative pathways leading to inactivation of the G1 restriction point or if they can occur in the same tumor, possibly exerting an additive effect on cancer progression. We investigated a series of 57 NSCLCs, analyzing cyclin D1 and RB at the gene and protein levels by Southern blot, Northern blot and immunohistochemistry. The cyclin D1 gene was amplified in 18 cases, cyclin D1 immunoreactivity was seen in 25 tumors. Amplification and expression were significantly associated. RB immunohistochemical expression was absent in 9 of 42 informative cases. RB mRNA expression was low to absent in 9 of 45 informative cases, cyclin D1 amplification was associated with normal RB mRNA, and cyclin D1 over-expression was associated with normal RB immunoreactivity, supporting the hypothesis that alterations of cyclin D1 and RB are alternative mechanisms by which tumor cells may escape the G1 restriction point. A concurrent alteration of RB and cyclin D1 was seen in a small subset of NSCLCs. Abnormalities of cyclin D1 and/or RB at the gene and/or expression level were present in more than 90% of cases, stressing that cyclin D1 and/or RB alterations represent an important step in lung tumorigenesis.

Carcinoma, Non-Small-Cell Lung↗

PubMed1998

FHIT and p53 gene abnormalities in bronchioloalveolar carcinomas. Correlations with clinicopathological data and K-ras mutations.

Bronchioloalveolar carcinoma (BAC) is a particular type of adenocarcinoma of the lung which accounts for up to 9 per cent of pulmonary malignancies. The aetiology and pathogenesis of this unique neoplastic disease are still unclear. Three histological subtypes of BAC have been recognized: mucinous, non-mucinous, and sclerosing. Of these, mucinous and sclerosing BAC have a worse prognosis than non-mucinous tumours. The different morphological patterns and clinical outcomes of the subtypes of BAC suggest differences in their biological behaviour. Previous reports have shown that the mucinous form of BAC is characterized by constant mutations at codon 12 of the K-ras gene, whereas the other two histotypes show a frequency of K-ras mutations which is not different from that observed in conventional lung adenocarcinomas. The present study of a series of 51 BACs, previously investigated for K-ras gene mutations, has evaluated the status of two other genes, p53 and FHIT, known to be frequently altered in non-small cell lung cancer. Loss of heterozygosity at microsatellite-containing loci located within the FHIT gene was observed in 22 (43 per cent) BACs. The distribution of FHIT gene abnormalities was not statistically different in the three histological subtypes. p53 mutations were present in 13 (32 per cent) non-mucinous/sclerosing BACs, while no mutations were seen in mucinous tumours (P = 0.039). Correlations with clinicopathological parameters showed that p53 mutations in BACs are associated with more aggressive tumours. No correlations were observed between FHIT or K-ras gene abnormalities and clinicopathological data. In conclusion, these results indicate that FHIT alterations are frequently involved in BAC tumourigenesis and that genetic changes in the p53 and K-ras genes can distinguish between different histotypes of BAC.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed1998

Evaluation of FHIT gene alterations in ovarian cancer.

The FHIT gene, recently cloned and mapped on chromosome 3p14.2, has frequently been found to be abnormal in several established cancer cell lines and primary tumours. As alterations of chromosome 3p are common events in ovarian cancers with breakpoint sites at 3p14.2, we decided to investigate the role of FHIT in human ovarian tumorigenesis. Fifty-four primary ovarian carcinomas were studied by reverse transcription of FHIT mRNA followed by polymerase chain reaction (PCR) amplification and sequencing of products. The same tumours and matched normal tissues were also investigated for loss of heterozygosity using three microsatellite markers located inside the gene. We found an abnormal transcript of the FHIT gene in two cases (4%) and allelic losses in eight cases (15%). Twelve (22%) of the 54 tumours investigated belonged to young patients with a family history of breast/ovarian cancer. In none of these cases was the FHITgene found to be altered. Our results indicate that FHITplays a role in a small proportion of ovarian carcinomas.

Acid Anhydride Hydrolases↗

PubMed1998

Genetic analysis of lung tumours of non-smoking subjects: p53 gene mutations are constantly associated with loss of heterozygosity at the FHIT locus.

Lung cancer is strictly associated with tobacco smoking. Tumours developed in non-smoking subjects account for less than 10% of all lung cancers and show peculiar histopathological features, being prevalently adenocarcinomas. A number of genetic data suggest that their biological behaviour may be different from that of lung tumours caused by smoking, however the number of cases investigated to date is too low to draw definitive conclusions. We have examined the status of p53 and K-ras genes and the presence of loss of heterozygosity (LOH) at the FHIT locus in a series of 35 lung adenocarcinomas that developed in subjects who had never smoked. Results were compared with those obtained in a series of 35 lung adenocarcinomas from heavy-smoking subjects. In the group of non-smoking subjects p53 mutations and LOH at the FHIT locus were present in seven (20%) cases, and the two alterations were constantly associated (P < 0.0001), whereas they were not related in the series of carcinomas caused by smoking. In tumours developed in heavy-smoking subjects, the frequency of LOH at the FHIT locus was significantly higher (P = 0.006) than in tumours from non-smoking subjects. The frequency of p53 mutations in adenocarcinomas caused by smoking was not different from that seen in non-smoking subjects. However, in the group of smoking subjects we observed mostly G:C --> T:A transversions, whereas frameshift mutations and G:C --> A:T transitions were more frequently found in tumours from non-smoking subjects. No point mutations of the K-ras gene at codon 12 were seen in subjects who had never smoked, whereas they were present (mostly G:C --> T:A transversions) in 34% of tumours caused by smoking (P = 0.002). Our data suggest that lung adenocarcinomas developed in subjects who had never smoked represent a distinct biological entity involving a co-alteration of the p53 gene and the FHIT locus in 20% of cases.

Acid Anhydride Hydrolases↗

PubMed1998

Cell cycle-related gene abnormalities and product expression in esophageal carcinoma.

In esophageal carcinoma, individual genetic alterations of cyclins, cyclin-dependent kinase inhibitors, and final effectors of the G1-to-S transition have been documented. Our aim was to design a comprehensive analysis of the role and clinical significance of some critical genes, namely cyclin D1, MTS1, and Rb. To this end, cyclin D1 gene amplification and protein accumulation, Rb gene allelic loss and protein expression, and MTS1 gene mutation and DNA methylation were investigated in a series of 74 esophageal carcinomas. Cyclin D1 amplification was documented in 17 of 55 (31 %) cases, being a feature of squamous cell type (14 of 17 amplified cases). Cyclin D1 accumulation significantly correlated with lymph node metastasis (p < 0.02), advanced tumor stage (p < 0.05), and a reduced overall survival rate (p < 0.03). Rb gene loss of heterozygosity occurred in 14 of 39 (36%) informative cases and was associated with an unfavorable survival rate (p < 0.01). MTS1 gene mutations were detected in 2 adenocarcinomas only; gene methylation was observed in 17 of 72 cases (24%) without any correlations with the variables investigated. A direct association between cyclin D1 and Rb gene accumulation (p < 0.0005) and an inverse one between RB loss of heterozygosity and MTS1 abnormalities (p < 0.05) emerged from this study. These results have important clinical implications because both cyclin D1 and Rb gene deregulation are significantly related to an unfavorable survival rate. In addition, cyclin D1 amplification is associated with esophageal carcinoma of squamous cell type, being totally absent in adenocarcinomas (p < 0.01). The combined evaluation of these genes also demonstrates that molecular abnormalities of genes belonging to the same pathway are mutually exclusive and unnecessary for the neoplastic transformation and tumor progression.

Carcinoma↗

PubMed1997

The chromosome location of the human homolog of the mouse mammary tumor-associated gene INT6 and its status in human breast carcinomas.

The INT6 gene is a common integration site for the mouse mammary tumor virus in mouse mammary tumors. We have determined that the human homolog of INT6 is located on chromosome region 8q22-q23. A processed INT6 pseudogene is located on chromosome 6q. INT6 is composed of 13 exons that span 45 kb of genomic DNA. The deduced amino acid sequence of the gene product is identical to the mouse protein and contains three potential translation start signals. We have examined 100 primary breast carcinoma DNAs for evidence of genetic alteration affecting INT6. Loss of heterozyosity (LOH) was detected in 11 of 39 (28%) of the tumor samples informative for a polymorphic sequence in intron 7 of INT6. Since single-strand conformation and hybrid mismatch analysis of the remaining allele in these tumor DNAs failed to detect any mutations, we conclude that the target gene for LOH must be closely linked to INT6.

Animals↗

PubMed1997

Association between cigarette smoking and FHIT gene alterations in lung cancer.

Epidemiologic data have strongly indicated that cigarette smoking is linked to the development of lung cancer. However, little is known of the molecular targets of carcinogens contained in tobacco smoke. To identify genetic lesions characteristic of tobacco damage, we undertook a molecular analysis of microsatellite alterations within the FHIT gene and FRA3B, as well as at an independent locus on chromosome 10, D10S197, in lung tumors from heavy smokers and in tumors from never smokers. Loss of heterozygosity affecting at least one locus of the FHIT gene was observed in 41 of 51 tumors in the smokers group (80%) but in only 9 of 40 tumors in nonsmokers (22%). The comparison between the frequency of losses in FHIT in smokers and nonsmokers was statistically significant (P = 0.0001), whereas no difference in loss of heterozygosity rate was observed at D10S197 locus. These findings suggest that FHIT is a candidate molecular target of carcinogens contained in tobacco smoke.

Acid Anhydride Hydrolases↗

PubMed1997

Cyclin-D1-gene amplification and expression in breast carcinoma: relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21WAF1 immunohistochemical expression.

Cyclin D1 is a major positive regulator of the G1 restriction point promoting inactivation of the retinoblastoma protein (RB). The cyclin D1 gene is rearranged, amplified and/or over-expressed in several human neoplasms. In the present series of 64 human breast carcinomas, cyclin D1 amplification (4- to 8-fold) was seen in 24% of cases, and cyclin-D1 immunohistochemical over-expression was seen in 50% of cases. Amplification and over-expression were statistically associated; however, divergent result were seen in 30% of cases. Some of these discrepancies may reflect the fact that cyclin-D1 expression may be due to mechanisms other than gene amplification. Cyclin-D1 over-expression, but not cyclin-D1 amplification, was associated with positive oestrogen-receptor immunoreactivity. Cyclin-D1 amplification was associated with high RB expression, and 4 cases (7%) with absent RB immunoreactivity showed no cyclin-D1 amplification nor expression. Our data support the hypothesis that cyclin-D1 amplification may be associated with enhanced gene transcription and with high RB expression, that high ER expression may cooperate in maintaining high levels of cyclin-D1 protein, and that loss of RB function, as assessed by the lack of RB immunoreactivity, may be related to normal cyclin-D1 gene copy number and low cyclin-D1 expression.

Blotting, Southern↗

PubMed1997

Alterations of P16 (MTS1) in node-positive non-small cell lung carcinomas.

The status of the P16 gene was investigated by Southern blot, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP), and DNA sequencing analyses in 30 primary resected non-small cell lung carcinomas (NSCLCs) with metastatic involvement of thoracic lymph nodes and 33 NSCLCs without node metastases. Direct sequencing of tumour DNA samples scored positive by PCR-SSCP showed five somatic mutations of the P16 gene: four nonsense and one frameshift. The Southern blot analysis revealed the presence of a homozygous deletion of the P16 locus in one tumour. All of the six NSCLCs with somatic aberrations of the P16 gene belonged to the series of tumours with metastatic diffusion to thoracic lymph nodes. In each of these six cases, the genetic aberration was seen in both the primary tumour and the node metastasis. No P16 alteration was found in tumours without metastatic lymph nodes. This difference was statistically significant (P = 0.02). No correlation was present between P16 alterations and other clinicopathological parameters including age of patients, tumour size, histological type, and grade. In three tumours with genetic aberration of P16, there was a concomitant alteration of the p53 gene. Our results indicate that the P16 gene is infrequently mutated (10 per cent of the cases examined) in primary resected NSCLC. However, since P16 mutations were found only in metastatic tumours, they may be important events in late phases of tumour progression and could represent useful markers of tumour aggressiveness in NSCLC.

Adult↗

PubMed1997

p53 alterations are predictive of chemoresistance and aggressiveness in ovarian carcinomas: a molecular and immunohistochemical study.

Chemotherapeutic management of ovarian cancers is a difficult task as these neoplasms show significant differences in chemosensitivity, even if they share identical clinicopathological features. The present study was undertaken to investigate the prognostic and predictive role of p53 alterations in ovarian cancer. To this end, using different technical approaches, i.e. genetic and immunohistochemical analyses, we analysed a series of 68 ovarian neoplasms including 15 low malignant potential (LMP) tumours and 53 invasive carcinomas. We never observed p53 abnormalities in LMP tumours. p53 alterations were present only in invasive ovarian carcinomas, and they were detected much more frequently in tumours characterized by high histological grade (P = 0.01) and advanced-stage disease (P = 0.006 and P = 0.05 for gene mutations and protein expression respectively). For 33 patients with invasive ovarian cancer, information was available concerning response to cisplatin-based chemotherapy. A strong correlation (P = 0.001) has emerged between p53 alterations and response to chemotherapy; only one (14%) of seven patients who had a pathological complete response to antiblastic drugs showed p53 aberrations, whereas 18 (82%) of 22 cases with partial response and all of the four non-responsive patients scored positive for p53 abnormalities. We also observed that patients with p53 mutations had a significantly shorter progression-free survival than patients with p53-negative tumours (P = 0.05). Taken together, our results strongly suggest that in epithelial ovarian malignancies tumours showing p53 aberrations are significantly less sensitive to chemotherapy and more aggressive than those with functional p53. Thus, a routine analysis of this gene could have profound implications for the treatment of ovarian cancer.

Antineoplastic Agents↗